Phytochemicals: Current strategies for treating breast cancer.

Females with early-stage metastatic, estrogen-dependent breast cancer are generally treated with surgery, radiation and chemotherapy, or with more targeted approaches such as aromatase inhibitors (anastrozole or letrozole) or anti-estrogens (tamoxifen). Despite widespread successful usage of these agents for the treatment of breast cancer, resistance, tumor relapse and metastasis remain the principal causes of mortality for patients with breast cancer. While numerous groups have made major contributions toward an improved understanding of resistance mechanisms, the currently insufficient grasp of the most critical pathways involved in resistance is evident in the inability to adequately treat and drastically improve patient outcomes in females with hormone-refractory breast cancer, including triple negative breast cancer. Therefore, further investigation of novel therapeutic approaches is paramount to reveal previously unconsidered agents that could be utilized to treat metastatic disease. Numerous naturally occurring phytochemicals have recently gained interest as potential therapeutic breast cancer agents appear to directly affect estrogen-dependent and estrogen-independent breast cancer cell proliferation, potentially via affecting breast cancer stem cell populations. While numerous natural compounds have exhibited promise, they are limited by their bioavailability. Therefore, to effectively treat future hormone-refractory breast tumors, it is critical to adequately refine and formulate these agents for effective therapeutic use and delivery. Herein, the literature on the current state of phytochemicals is reviewed, including their limitations and potential as targeted therapies for breast cancer.

Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1.

Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a -3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer.